Biological interactions, such as protein:protein interactions, protein:nucleic acid interactions, and protein:ligand interactions are involved in a wide variety of processes occurring in living cells. For example, agonism and antagonism of receptors by specific ligands may effect a variety of biological processes such as gene expression, cellular differentiation and growth, enzyme activity, metabolite flow and metabolite partitioning between cellular compartments. Undesirable or inappropriate gene expression and/or cellular differentiation, cellular growth and metabolism may be attributable, at least in many cases, to biological interactions involving the binding and/or activity of proteinaceous molecules, such as transcription factors, peptide hormones, receptor molecules, and enzymes.
Peptides present potential therapeutic and prophylactic agents for many human and animal diseases, biochemical disorders and adverse drug effects, because they can interact highly specifically with other molecules. Thus, mimetic peptides have been designed and developed based on three dimensional protein structures. For example, many proteins recognize nucleic acids, other proteins or macromolecular assemblies using a partially exposed alpha helix. Within the context of a native protein fold, such alpha helices are usually stabilized by extensive tertiary interactions with residues that may be distant in primary sequence from both the alpha helix and from each other. With notable exceptions (Armstrong et al., 1993, J. Mol. Biol., 230: 284-291), removal of these tertiary interactions destabilizes the alpha helix and results in molecules that neither fold nor function in macromolecular recognition (Zondlo et al., 1999, J. Am. Chem. Soc., 121: 6938-6939). The ability to recapitulate or perhaps even improve on the recognition properties of an alpha helix within the context of a small molecule may find utility in the design of synthetic mimetics or inhibitors of protein function (Cunningham et al., 1997, Curr. Opin. Struct. Biol., 7:457-462) or new tools for proteomics research.
Proteins generally recognize each other using large and shallow complementary surfaces. Therefore, small proteins (miniature proteins) with well-defined three-dimensional structures and finely tuned functional properties are perhaps ideally suited for protein surface recognition and disruption of protein:protein interaction. Clearly, there is a need for developing the miniature proteins (in particular, those with high affinity and high specificity for a target molecule) as therapeutics and prophylactics.